Dr Zeinab Khalil

ARC Research Fellow

Institute for Molecular Bioscience
z.khalil@uq.edu.au
+61 7 334 62980

Overview

I completed my PhD in 2013 and I am currently a Senior Research Fellow and the Managing Director of the Soils of Science (S4S) Program at the University of Queensland. I am recognised as an emerging leader in antibiotic biodiscovery research. I have multidisciplinary research skills and expertise spanning the fields of organic chemistry and microbiology. I have made a significant contribution to the field of microbial biodiscovery employing high-throughput, high efficiency, natural product discovery to explore the chemical and biological properties of natural products produced by Australian marine and terrestrial microbes. I have identified and evaluated >40 new drugs targeting infectious diseases that attracted >$3M in research funding. I have led multi-year projects with industry, targeting animal health (ELANCO) and crop (NEXGEN Plants) and microbial chemical diversity (Microbial Screening Technologies; BioAustralis). I am a co-inventor on a UQ pending patent application documenting a new soil microbiome-inspired crop protection agent. This invention has attracted industry investment (NEXGEN Plants), to establish its potential, ahead of licensing and commercialisation. Therefore, I have co-led a project with industrial partner NEXGEN Plants, to investigate a new natural product that activates innate plant immunity defences against significant pathogens (patent pending). Since 2015, I have established the antibiotic biodiscovery capability at IMB targeting multidrug resistant (MDR) human pathogens and developed new approaches that have had significant knowledge impact in the antibiotic development and host defence research areas directed to combat MDR pathogens. This has resulted in the establishment of the Biodiscovery@UQ facility, a university-wide networking initiative designed to support excellence in biodiscovery research across UQ. I have secured funding from UQ to develop a new antitubercular drug lead (CIA), an ARC Linkage grant (LP19, CIB) to develop new anthelmintics and a grant from the University de La Frontera (collaborator), Chile to discover new antibiotics from Antarctic microbes, Marine CRC fund (CIA) to map the chemical diversity in Australian marine microbes and ARC LIEF grant. I co-led THE FIRST citizen science initiative, S4S, including developing the APP, website and running regional public workshops, with the aim of increasing public awareness about the role of soil microbes in antibiotic discovery. This initiative has attracted ~$1M in institutional and philanthropic support.

Research Interests

  • Cultivation Profiling (MATRIX)
    An innovative high throughput miniaturized 24-well plate technology for the analytical cultivation of fungi and bacteria (MATRIX), supportive of multiple culture media and additive conditions, under broth static, broth shaken and solid phase. The MATRIX greatly accelerates, lowers the cost and increases the productivity of our microbial biodiscovery research.
  • Chemical Profiling (UPLC-QTOF and GNPS)
    An in situ MATRIX extraction to support rapid UPLC-DAD and UPLC-QTOF (MS/MS) profiling of crude extracts (and chromatographic fractions and pure metabolites), and data visualisation using global natural products social networking (GNPS) protocols. This greatly enhances our capacity to (i) assess chemical diversity in crude extracts/fractions, (ii) detect new from known, rare from common, and related from unrelated natural products, and (iii) detect transcriptional activation of silent biosynthetic gene clusters.
  • Nitric oxide mediated transcriptional activation (NOMETA)
    The use of nitric oxide as a transcriptional activator of silent biosynthetic gene clusters (BGCs) that code for bacterial and fungal defensive chemistry, including new classes of antibiotic and antiparasitic. This process allows for the addition of either (a) very low (sub nM) levels of Gram –ve bacteria lipopolysaccharide to fungal cultures to induce nitric oxide release, or (b) the direct addition of very low levels of an NO donor such as sodium nitric prusside to bacterial or fungal cultures, to induce the activation of silent BGCs encoded with microbial genomes.
  • Microbial Biodiscovery and metabolite expression profiling
    Many past studies into microbial secondary metabolism gene activation (autoregulators) have relied heavily on (i) the observation of morphological differentiation (which may or may not be linked to activation of new secondary metabolism), (ii) the up-regulation of a known metabolite/antibiotic(s) (which does not address the activation of silent “new” genes), or (iii) the appearance of pigmentation or antibiotic activity (which cannot differentiate new from old chemistry). A high throughput modern approach to the detection of gene activation events needs to rapidly and directly assess metabolite profiles. This project will develop and implement innovative methodologies and protocols for the HPLC-DAD-ELSD-HRMS analysis of >1M microbial metabolites – characterized by retention time, UV-vis spectrum and MW plus elemental composition. These analyses will be facilitated by the use of semi-automated and automated systems, including data archival and profiling software, to annotate, compare and evaluate similarities and differences in metabolite expression. This innovation implements a high throughput approach to detecting gene activation events by directly observing and providing a qualitative and quantitative assessment of microbial secondary metabolite production. This approach can be used to (i) detect, (ii) guide the isolation of, and (iii) evaluate the impact of, new gene activators, and their activated gene products.
  • Gene activators
    Whereas most microbial biodiscovery seeks to isolate new bioactive secondary metabolites produced under standard fermentation conditions, this project is innovative in that it seeks to challenge the microbial genome and activate otherwise silent secondary metabolite gene clusters. While this project will undoubtedly discover new microbial secondary metabolites, the main objective of the project is to discover and evaluate microbial metabolites that activate secondary metabolism – gene activators. This innovation addresses the unmet need to discover gene activators and assess their value in both basic science - as molecular probes to better understand microbial genomics and systems biology - as well as applied science – as molecular reagents to switch on “silent” microbial secondary metabolite gene clusters.
  • Antibiotic and Cytotoxicity Profiling
    Quantitative antibiotic screening against multiple Gram +ve and –ve bacteria, and fungi, including multidrug resistant clinical isolates such as methicillin resistant Staphylococcus aureus and Mycobacterium tuberculosis, as well as cytotoxicity screening against multiple mammalian (human) cancerous and non-cancerous cell lines, including multidrug resistant cancer cells over-expressing ABC transporter efflux pumps. This screening allows us to rapidly assemble a bioactivity profile on all prospective extracts.

Research Impacts

In 2019, > 1.2 M people worldwide died from multidrug resistant (MDR) bacterial infections due to the lack of effective antibiotics, and we are in desperate need of chemical inspiration, to replenish the antibiotic pipeline. Our Antimicrobial Research and Development program has contributed significant NEW KNOWLEDGE through applying medicinal chemistry to the discovery of translational solutions to antimicrobial resistance (>100 new antibiotics) as well as novel basic research tools to help better understand the interactions between antibiotics and resistant bacteria. Specifically, our program has applied novel transcriptomics approaches to identify and activate silent genes within the microbial genome that informed the development of effective antibiotics.

Qualifications

  • Doctor of Philosophy, The University of Queensland
  • Master of Microbiology, Helwan University
  • Bachelor of Pharmaceutical Sciences (Hons), Helwyn University

Publications

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Supervision

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Available Projects

  • Soils for Science (S4S) seeks to build a partnership between UQ researchers and the public, to fast-track the discovery of new antibiotics. S4S will engage pastoralists, farmers, homeowners, schools and others, to assemble a collection of 100,000 Australian soil samples, from which we will recover a living library of >2,000,000 microbes (bacteria and fungi) rich in new antibiotics, including against important crop pathogens.

    This project seeks to discover the next generation of new antibiotics against multi-drug resistant pathogens.

  • This project seeks to develop advanced and optimised methods in UPLC-QTOF-MS/MS molecular networking, to rapidly, cost effectively, reproducibly and quantitatively map the small molecule and peptide chemical diversity of taxonomically and geographically diverse Australian marine microbes and microalgae, including fresh and processed biomass, biorefinery fractions and outputs, and formulated marine bioproducts – to advance the discovery and development of valuable new marine bioproducts.

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Publications

Book Chapter

Journal Article

Conference Publication

Other Outputs

Grants (Administered at UQ)

PhD and MPhil Supervision

Current Supervision

Completed Supervision

Possible Research Projects

Note for students: The possible research projects listed on this page may not be comprehensive or up to date. Always feel free to contact the staff for more information, and also with your own research ideas.

  • Soils for Science (S4S) seeks to build a partnership between UQ researchers and the public, to fast-track the discovery of new antibiotics. S4S will engage pastoralists, farmers, homeowners, schools and others, to assemble a collection of 100,000 Australian soil samples, from which we will recover a living library of >2,000,000 microbes (bacteria and fungi) rich in new antibiotics, including against important crop pathogens.

    This project seeks to discover the next generation of new antibiotics against multi-drug resistant pathogens.

  • This project seeks to develop advanced and optimised methods in UPLC-QTOF-MS/MS molecular networking, to rapidly, cost effectively, reproducibly and quantitatively map the small molecule and peptide chemical diversity of taxonomically and geographically diverse Australian marine microbes and microalgae, including fresh and processed biomass, biorefinery fractions and outputs, and formulated marine bioproducts – to advance the discovery and development of valuable new marine bioproducts.